GB2074567A

GB2074567A - Platinum-amine complexes

Info

Publication number: GB2074567A
Application number: GB8110578A
Authority: GB
Original assignee: Shionogi and Co Ltd
Current assignee: Shionogi and Co Ltd
Priority date: 1980-04-30
Filing date: 1981-04-03
Publication date: 1981-11-04
Also published as: DE3117216A1; JPS56154493A; US4359425A; IT8167551A0; FR2481696A1

Description

1

GB 2 074 567 A 1

SPECIFICATION Organo-platinum complex

This invention relates to certain organo-platinum complexes having antitumour activity.

It is known that some kinds of platinum complexes have antitumour action. In particular, cisplatin 5 [cisdiamminedichloroplatinum (II)] has been used clinically in the treatment of malignancy, for example, 5 disseminated testicular and ovarian carcinoma. Cisplatin, however, has serious side effects such as renal toxicity, myelosuppression and ototocicity. In recent times the occurrence of malignancy and the resulting death rate have been on the increase, and it is desirable to develop antitumour agents of strong activity but lesser toxicity. The chemical modification of platinum complexes has been attempted 10 extensively. Examples of the platinum complexes disclosed in the literature are malonato (1,2- 1 q diaminocyclohexane) platinum (II) [Japanese Unexamined Patent Publication No. 53-31 648] and sulfato (1,2-diaminocyclohexane) platinum (II) [Japanese Unexamined Patent Publication No. 54-44620].

According to the invention there is provided a complex of the formula:

(ch.)

15

wherein X and Y each independently, or when considered together, a mono- or bi-functional ligand selected from halogeno, nitrato, sulfonate, monocarboxylato (mono-functional), sulfato and dicarboxylato (bi-functional); and n and m each independently is an integer 1 or 2.

In the above definition, "halogeno" includes chloro, bromo and iodo, preferably chloro. 20 "Sulfonato" includes C, to C5 alkanesulfonato and C6 to C8 arylsulfonato. Representative C, to C5 alkanesulfonato groups are methanesulfonato, ethanesulfonato, propanesulfonato,

isopropanesulfonato, butanesulfonato, isobutanesulfonato, sec-butanesulfonato, t-butanesulfonato and pentanesulfonato. Representative C6 to Cs arylsulfonato groups are benzenesulfonato, toluenesulfonato and xylenesulfonato. "Monocarboxylato" means saturated or unsaturated C, to C7 monocarboxylato, 25 including, for example, formato, acetato, propionato, butyrato, isobutyrato, valerate, acrylato,

proprionato, methacrylato, crotonato and isocrotonato. The preferred monocarboxylato groups are C2 to C6 monocarboxylato groups, most preferably acetato. "Dicarboxylato" means saturated or unsaturated C2 to C10 dicarboxylato groups, including for example, oxalato, malonato, succinato, maleato, fumarato, phthalato and hemimellitato, preferably oxalato, malonato or hemimellitato. The monocarboxylato and 30 dicarboxylato groups may optionally be substituted by halogen or hydroxy, e.g. as in chloroacetato, gluconato and glucuronato, and such groups are also intended to be included in the scope of the definition given above.

In the above formula (I), when n differs from m, the configuration of the amino groups on the bicyclic structure is exo-cis or trans.

35 Examples of the compounds (I) of the invention are as follows:

1) dichloro [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II);

2) dinitrato [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II);

3) sulfato [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II);

4) malonato [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II);

"40 5) bis(chloroacetato) [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II);

6) hemimellilato [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II);

7) oxalato [exo,cis-2,3-diaminobicyclo(2.2.1 (heptane] platinum (II);

8) bis(glycolato) [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II);

9) bis(glucuronato) [exo,cis-2,3-diaminobicyclo(2.2.1 Jheptane] platinum (II); 45 10) dichloro [exo,cis-2,3-diaminobicyclo(2.2.2)octane] platinum (II); and

11) bis(gluconato) [exo,cis-2,3-diaminobicyclo(2.2.2)octane] platinum (II).

The compounds of [1] of this invention may be prepared from compounds of the following formula til]:

20

25

oU

'I3H~ 0C0CHo J 3

NH- OCOCH^ J J

50 wherein n and m are as defined above.

[II]

50

GB 2 074 567 A

1) In the case when X and Y (formula [1 ]) are each halogen:

Compounds [II] may be reacted with alkali metal tetrahalogenoplatinate (II) salts to give the compounds [la] (in which X and Y are each halogen). It is preferred to employ the potassium salts as the alkali metal tetrahalogenoplatinate (II) salts. This reaction proceeds under weak alkaline conditions and 5 is preferably carried out in the presence of sodium bicarbonate. It ordinarily takes from 5 to 10 hours to 5 complete this reaction.

2) In the case of X and/or Y (formula[l]) being nitrato:

Compounds [la] may be reacted with silver nitrate in an aqueous medium to give compounds [I]

wherein X and/or Y are nitrato. When one molar equivalent of silver nitrate is employed relative to the ■■

10 amount of compounds [la], compounds [lb] (in formula [I] either X or Y is nitrato) result, and when two 10 molar equivalents of silver nitrate are employed, compounds [Ic] (in formula [I] both X and Y are nitrato)

result. This reaction is carried out with protection from light and is usually completed within a period of from 2 to 5 days.

3) In the case of X and/or Y (formula [I]) being sulfonato:

15 Compounds [la] may be reacted with a silver sulfonate, for example, silver methanesulfonate or 15 silver benzenesulfonate, to give compounds [I] wherein X and/or Y are/is sulfonato. When one molar equivalent of silver sulfonate is employed relative to the amount of compounds [la], compounds [Id] (in formula [I] either X or Y is sulfonato) result, and when two molar equivalents of silver sulfonate are employed, compounds [le] (in formula [I] both X and Y are sulfonato) result.

20 4) In the case when X and Y considered together represent sulfato: 20

Compounds [la] may be reacted with silver sulfate to give compounds [If] (in formula [I] X and Y considered together represent sulfato). It is preferred to effect this reaction at room temperature with protection from light, and the reaction is completed within a period of from 1 to 3 days.

5) In the case when one of X and Y is nitrato and the other is monocarboxylato:

25 Compound [Ic] may be reacted with alkali metal salts of monocarboxylic acids to give compounds 25 [Iq] (in formula [I] either X or Y is nitrato and the other is monocarboxylato). It is preferred to use one molar equivalent of said alkali metal salt relative to the amount of [Ic].

6) In the case when X and Y each or considered together represent monocarboxylato or dicarboxylato:

30 Compounds [Ic] may be reacted with monocarboxylic acids, dicarboxylic acids, or alkali metal salts 30

thereof in water to give compounds [Ih] (in formula [I] X and Y each are monocarboxylato, or X and Y considered together represent dicarboxylato). This reaction may be carried out with cooling or heating and is ordinarily completed within a period of from several minutes or tens of minutes to several days,

which time depends upon the species of carboxylic acid used and the variation and number of the

35 substituents. 35

The starting compounds [II] noted above are readily prepared from compounds of formula [III]

shown below according to the procedure described in Journal of the American Chemical Society, 89, 3005 (1967):

(CI- ; [ill]

40 wherein n and m are as defined above. 40

Compounds [III] are well-known compounds, among which compounds [III] (m=n=1) have been disclosed in Tetrahedron Letters 1968, 2789, compounds [III] (m=2 and n=1, or m=1 and n=2) are commercially available as 2-norbornene, and compounds [III] (m=n=2) have been disclosed in Journal of the American Chemical Society, 76, 5396 (1954).

45 The compounds [I] of this invention have potent antitumour activity. Thus, for example, the 45

activities of some representative compounds [lj of this invention are shown below.

Test Method

Mouse Leukaemia L 1210 ascites cells (105 cells) were intraperitoneally inoculated into BDF,

mice. On the next day, the predetermined amount of the test compounds shown below was 50 administered. Eight to ten mice were employed in a control group, and four to seven mice were 50

employed in a test group.

Evaluation of the effect

From the average number of days survival in the test group and those of the control group the

3

GB 2 074 567 A 3

increase of life-span (ILS) was calculated according to the following expression:

Average survival days Average survival days in test group — in control group

ILS(%)= x 100

Average survival days in control group

Test compounds

(1) dichloro [exo,cis-2,3-diaminobicyclo(2.2.1 (heptane] platinum (II)

- 5 (2) dinitrato [exo,cis-2,3-diaminobicyclo(2.2.1 (heptane] platinum (II) 5

(3) sulfato [exo,cis-2,3-diaminobicyclo(2.2.1 (heptane] platinum (II)

(4) oxalato [exo,cis-2,3-diaminobicyclo(2.2.1 (heptane] platinum (II)

(5) malonato [exo,cis-2,3-diaminobicyclo(2.2.1 (heptane] platinum (II)

(6) bis(glucuronato) [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II)

10 Comparative compounds 10

(7) dichloro (cis-diamine) platinum (II)

(8) dichloro (1,2-diaminocyclohexane) platinum (II)

Result

Test Compound

Dosage (mg/kg)

Numbers of mice employed

ILS (%)

Numbers of survivors over 30 days

0 x 1

8

1 x 1

7

25

(1)

2 x 1

7

51

5 x 1

7

>126

2

10 x. 1

7

>143

3

20 x 1

7

-21

0 x 1

8

1 x 1

7

32

(2)

2 x 1

7

51

5 x 1

7

80

10 x 1

7

>151

4

20 x 1

7

-18

0 x 1

8

1 x 1

7

21

(3)

2 x 1

7

31

5 x 1

7

48

10 x 1

7

>221

5

20 x 1

7

-35

0 x 1

10

1 x 1

7

3

(4)

2 x 1

7

13

5 x 1

7

>54

1

10 x 1

7

>79

1

20 x 1

7

>149

4

0 < 1

7

5 x 1

7

16

(5)

10 x 1

7

20

20 x 1

7

31

50 x 1

5

>84

1

100 x 1

7

-18

4

GB 2 074 567 A 4

Test Compound

Dosage (mg/kg)

Numbers of mice employed

ILS (%)

Numbers of survivors over 30 days

(6)

0 x 1

10

1 x 1

7

4

2 x 1

7

17

5 x 1

7

27

10 x 1

7

>67

1

20 x 1

7

>126

2

50 x 1

7

>43

1

(7)

0x1

10

1 x 1

7

9

2 x 1

7

11

5 x 1

7

29

10 x 1

7

>84

1

20 x 1

4

-26

(8)

0 x 1

10

1 x 1

7

15

2 x 1

7

20

5 x 1

7

>67

1

10 x 1

7

>129

2

20 x 1

7

-7

*

10

15

20

As can be seen from the above, the tested compounds [I] have potent anti-tumour activity. The compounds [I] of this invention can be administered parenteraliy to humans or animals in the treatment of various kinds of malignancy. In use, the compounds [I] may be dissolved or suspended in a suitable solvent for injection (e.g. distilled water for injection, isotonic sodium chloride solution, ethanol, 5 glycerin, propylene glycol, olive oil or peanut oil), and administered intravenously, intramuscularly or subcutaneously. In preparations for injection, the compounds [I] may be contained in ampoules in the form of solution or suspension; alternatively, it can also be appropriate to keep the compounds [I] in ampoules or vials in the form of, for example, crystals, powder, microcrystals or lyophilizate and to dissolve or suspend immediately before using. If necessary, stabilizing agents may be added. 10

When used in the treatment of tumours, the compounds [I] may be administered parenteraliy to an adult in single or divided doses of from 1 to 100 mg 1 to 3 times a day. It is, of course, appropriate optionally to increase or decrease the dosage according to the age, condition or anamnesis of the patient. Thus, the invention also provides a pharmaceutical or veterinary formulation comprising a complex of formula [I] formulated for pharmaceutical or veterinary use, respectively, such formulations 15 may be in unit dosage form and may also comprise pharmaceutically acceptable or veterinarjly acceptable diluents, carriers or excipients.

Furthermore, the invention also embraces the complexes [I] or the above formulations for use in producing an antitumour effect in an animal (i.e. when in a "get up" suitable for producing such an effect or when intended to produce such an effect, e.g. when supplied with appropriate instructions). 20 The following Examples are provided further to illustrate and describe this invention.

EXAMPLE 1

Dichloro [exo,cis-2,3-diaminobicyclo(2.2.J)heptane] platinum (II)

r~-r^r-nh3 ococh3

m

NH^ OCOCH^

KgPtCl^

r-r^T--'NH2X /C1

pt(n) / \

•nh ci

2

OX,

25 To a solution of diaceto exo,cis-2,3-diaminobicyclo(2.2.1 )heptane 7 (300 mg; 1.22 mmoles) in water (3 ml) are added a solution of potassium tetrachloroplatinate (II) (468 mg; 1.23 mmoles) in water (6 ml) and then solid sodium bicarbonate (206 mg; 2.45 mmoles), and the mixture is shaken, by which carbon dioxide is vigorously generated. After subsidence of carbon dioxide evolution, the reaction

25

5

GB 2 074 567 A 5

mixture is stirred at room temperature for 8 hours. The resulting solid is collected by filtration, washed with water, acetone, and then ether, and dried under reduced pressure to give the title compound 2 (303 mg) as pale yellowish green crystals (first crop). The mother liquor is allowed to stand overnight to give an additional crop of the title compound 2 (49 mg) as yellow crystals (second crop).

5 Total yield 352 mg (74%) 5

mp. > 300°C.

Elemental Analysis:

Calcd (for C7H14N2PtCI2) (%):

C, 21.44; H, 3.60; N, 7.14;

10 Found (%):

C, 21.40; H, 3.50; N, 6.94;

IR: v Nui°' 3205,3110 (—NH,) cm"1.

max ■L

EXAMPLE 2

Dinitrato [exo,cis-2,3-diaminobicyclo(2.2.1/heptane] platinum (II)

2

CI, 18.08. CI, 18.16.

10

15

^NH„

(TO

,ci

Pt(n) NH„// ^ CI

AgNO,

To a suspension of Compound 2 (392 mg; 1 mmole) in water (35 ml) is added silver nitrate (340 mg; 2 mmoles), and the reaction vessel is wrapped in a sheet of aluminium foil in order that the reaction mixture is shielded from light. The mixture is stirred for 3 days, and the resulting colourless precipitate (silver chloride) is removed by filtration. The excess amount of silver nitrate remaining in the filtrate is 20 decomposed with 0.5% aqueous solution of potassium chloride, which is added to the filtrate until no 20 turbidity results. The filtrate is evaporated to dryness with a rotary evaporator, and the resulting residue is dried at nearly 55°C under reduced pressure to give the title compound 3 (384 mg) in 86% yield, m.p. about 200°C (decomposition)

Elemental Analysis:

25 Calcd (for C7H14N406Pt) (%):

C, 18.88; H, 3.17; N, 12.58.

Found (%):

C, 18.32; H, 3.24; N, 12.32.

IR: v Nuj°' 3240, 3150 (—NH,), 1466, 1274 (—NO,) cm"', max 2 3

30 EXAMPLE 3

Sulfato [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane]platinum (II)

r/ ] jpt(u) > I / I Pt(n) so.

2 U

To a suspension of Compound 2 (275 mg; 0.7 mmole) in water (30 ml) is added silver sulfate (218 mg; 0.7 mmole), and the mixture is stirred at room temperature for 2 days under protection from light, 35 and then worked up in the same manner as in Example 2 to give the title compound 4 (260 mg) as a 35 yellow material in 80% yield.

mp. about 230°C (decomposition)

Elemental Analysis:

Calcd (for C7H14N204SPt) (%):

40 C, 20.15; H,3.38; N,6.71; S, 7.68. 40

Found (%):

C, 18.14; H, 3.67; N, 6.30; S, 7.61.

6

GB 2 074 567 A 6

IR: max ~3180, ~3080, (—NH2), 1110, 1023, 940 (—S04) cm"1. EXAMPLE 4

Malonato [exo,cis-2,3-diaminobicycio(2.2.1)heptane] platinum (II)

n°3

\( | Pt(lX)

1 \ 1 / \ CH xCOONa H 0

»»3 "'COONa ' 2

2

^ JO-CO

2

5 Compound 3 (400 mg; 0.9 mmole) is dissolved in water (20 ml) with heating at 95°C. A solution 5

of sodium malonate monohydrate (150 mg; 0.9 mmole) in water (3 ml) is added thereto, and the mixture is allowed to stand at room temperature for 10 to 12 minutes to yield colourles crystals as a precipitate. The reaction mixture is cooled with ice for nearly complete crystallization. The resulting colourless crystals are collected by filtration to give the title compound 5 (287 mg) (first crop). The 10 mother liquor is further concentrated to about 3 ml and allowed to stand overnight to give an additional 10 crop of the title compounds (38 mg) (second crop).

Total yield: 325 mg (85%)

mp. about 240°C (decomposition)

Elemental Analysis:

15 Calcd (for C10H16N204Pt) (%) 15

C, 28.37; H,3.81; N, 6.62.

Found (%):

C, 27.78; 1-1,3.71; N, 6.66.

IR: v Nujo1 3175, 3115 (—NH,), 1662, 1623 (—C=0) cm"1.

max 11

20 i EXAMPLE 5 20

Bis(chloroacetato) [exo,cis-2,3-diaminobicyclo(2.2.1)heptane] platinum (II)

NH^ ^/N°3

t(ll)

2x_>

\ CICH-COOH

NH2 N03 2

^-NH„ .0C0CH„C1

NH2 0C0CH2C1

Compound 3 (60 mg; 0.135 mmole) is dissolved in water (3 ml) with heating, and the resultant solution is cooled to room temperature, mixed with chloroacetic acid (86 mg:0.9 mmole), and allowed 25 to stand in a refrigerator for 3 days. The separated crystals are collected by decantation, washed with a 25 small amount of cold water, and dried under reduced pressure to give the title compound 6 (24 mg) containing water of crystallization (35% yield). This is repeatedly recrystallized from methylene chloride-hexane in order that the water of crystallization may be removed.

mp. 153—156°C (decomposition)

7

GB 2 074 567 A 7

Elemental Analysis:

Calcd (forC11H18N204CI2Pt) (%):

C, 25.99; H,3.57; N, 5.51.

Found (%):

5 C, 25.48; H, 3.54; N, 5.57.

Nuiol

IR: v ' 3195, 3100 (—NH2), 1621cm-1.

IlidX

EXAMPLE 6

Hemimellilato [exo,cis-2,3-diaminobicyclo(2.2.1)heptane] platinum (II)

COOH

HOO

gx ym3 HOOC

Pt(n) —

\

NHg

2 COOH

ccc

NH_ OCO.

2N , /

Vt(n) [O nh^ nsoco/

10 Compound 3 (48 mg; 0.108 mmole) and hemimellitic acid (22.7 mg; 0.108 mmole) are dissolved 10 in water (1.2 ml) with heating, and the resultant solution is allowed to stand at room temperature. After 10 to 15 minutes, the colourless solid is precipitated. After 5 hours, the precipitate is collected by decantation and washed twice with a small amount of water to give the title compound 7(10 mg) in 17% yield.

15 mp. about 200°C (decomposition) 1 5

Elemental Analysis:

Calcd (for C16H18N206Pt) (%)

C, 36.30; H, 3.43; N, 5.29.

Found (%):

20 C, 32.84; H, 3.60; N, 5.54. 20

IR: v ~1!°l3400, (—OH), -3200, -3090 (—NH,), 1710, 1603, 1 576 (—C=0) cm'1.

max

EXAMPLE 7

Oxalato [exo,cis-2,3-diaminobicyc!o(2.2.1)heptane] platinum (II)

\o3 <C00Na>:

2

-NH2\ /°-C

/Pt(xx) SNH 0-C

2 »

8 0

25 To a solution of Compound 3 (178 mg; 0.4 mmole) dissolved in water (5 ml) under heating is 25

added a solution of sodium oxalate (54 mg; 0.4mmole) in water (5 ml). The mixture is allowed to stand at room temperature and the precipitated crystals are collected by filtration to give the title compound 8 (122 mg) in 75% yield.

mp. 290-—295°C (decomposition)

30 Elemental Analysis: 30

Calcd (for C9H14N204Pt) (%):

C, 26.41; H, 3.45; N, 6.84.

Found (%):

C, 26.35; H, 3.55; N, 6.75.

Nujol max

35 IR:i'mJv 3210,3110, (—NH2), 1695, 1664 (—C=0) cm"1. 35

8

GB 2 074 567 A 8

EXAMPLE 8

Bis(glycolato) [exo,cis-2,3-diaminobicyclo(2.2.1)heptane] platinum (II)

r-7^-/N03 /

ex /' \ —- cdc /pt(liv nhg n03 xnh2 ocochgoh

2 2

Compound 3 (91 mg; 0.2 mmole) and sodium glycolate (39 mg; 0.4 mmole) are dissolved in 5 water (6 ml) with heating, and the resultant solution is heated at 70°C for 6 hours. Most of the solvent 5 is evaporated under reduced pressure and the residue is mixed with a large amount of alcohol. The resultant colourless precipitate is collected by filtration and dried under reduced pressure to give the title compound 9 (31 mg) in 33% yield.

mp. 210—215°C (decomposition)

10 IR: v ^u^°' 3210, 3130 (—NH2), 1618 (—C=0) cm-1. 10

max

EXAMPLE 9

Bis(glucuronato) [exo,cis-2,3-diaminobicyc/o(2.2. Dheptane] platinum (II)

nx>o crx><"

^ nh2 n°3 2rcoona nh2 coor

XO

R=-CH-(CHOH)3-CHOH

To a solution of Compound 3 (437 mg; 0.982 mmole) dissolved in water (40 ml) under heating is 15 added sodium diglucuronate monohydrate (468 mg; 2.00 mmoles), and the mixture is allowed to stand 15 at room temperature for 30 minutes and evaporated to dryness with a rotary evaporator. The residue is washed with hot anhydrous ethanol (about 40 ml), dissolved in methanol, and concentrated, and the precipitated colourless solid is collected by filtration to give the title compound 10 (650 mg) in 94%

yield.

20 m.p. 155°C (decomposition) 20

Elemental Analysis:

Calcd (for C19H32N2014Pt) (%):

C, 32.25; H,4.56; N,3.96.

Found (%):

25 C, 29.32; H.4.86; N,3.95. 25

IR: v ^3300 (—OH), 3219, 3114 (—NH,), 1620 (—C=0) cm-1.

max

Claims

1. An organo-platinum complex of the formula:

30 wherein X and Y are each independently, or when considered together, a mono- or bi-functional ligand 30 selected from halogeno, nitrato, sulfonato, monocarboxylato (mono functional), sulfato and dicarboxylato (bi-functional); the monocarboxylato and dicarboxylato groups optionally being substituted by halogen or hydroxy; and n and m each independently is 1 or 2.

2. A complex as claimed in claim 1, wherein one of n and m is 1 and the other of n and m is 2.

35

3. A complex as claimed in claim 1 or claim 2, wherein X and Y are each halogeno. 35

9

GB 2 074 567 A 9

4. A complex as claimed in claim 1 or claim 2, wherein X and Y are each nitrato.

5. A complex as claimed in claim 1 or claim 2, wherein X and Y are each chloroacetato.

6. A complex as claimed in claim 1 or claim 2, wherein X and Y are each glycolato.

7. A complex as claimed in claim 1 or claim 2, wherein X and Y are each glucuronato.

5

8. A complex as claimed in claim 1 or claim 2, wherein X and Y considered together represent 5

sulfato.

9. A complex as claimed in claim 1 or claim 2, wherein X and Y considered together represent oxalato.

10. A complex as claimed in claim 1 or claim 2, wherein X and Y considered together represent

TO malonato. 10

11. Dichloro [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II).

12. Dinitrato [exo,cis-2,3-diaminobicyclo(2.2.1 Jheptane] platinum (II).

13. Sulfato [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II).

14. Malonato [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II).

15 15. Bis(chloroacetato) [exo,cis-2,3-diaminobicyclo(2.2.1)heptane] platinum (II). 15

16. Hemimellitato [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II).

17. Oxalato [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II).

18. Bis(glycolato) [exo,cis-2,3-diaminobicycio(2.2.1)heptane] platinum (II).

19. Bis(glucuronato) [exo,cis-2,3-diaminobicyclo(2.2.1 )heptane] platinum (II).

20 20. Dichloro [exo,cis-2,3-diaminobicyclo(2.2.2)octane] platinum (II). 20

21. Bis(gluconato) [exo,cis-2,3-diaminobicyclo(2.2.2)octane] platinum (II).

22. A complex as claimed in claim 1 or claim 2, wherein X and/or Y are/is selected from groups referred to hereinbefore in exemplification of X and/or Y.

23. A process for preparing a complex as claimed in claim 1, which process comprises reacting a

25 compound of the formula: 25

(CV. Wn

-nh3 ococh^

-nh3 0c0ch3

30

35

with an alkali metal tetrahalogenoplatinate so as to produce a complex as claimed in claim 1 wherein X and Y are each halogen, and, optionally, reacting said complex as claimed in claim 1 wherein X and Y are each halogen with silver nitrate and/or a silver sulfonate, or silver sulfate, so as to produce a complex as claimed in claim 1 in which at least one of X and Y is nitrato or at least one of X and Y is sulfonato or X and Y considered together represent sulfato, and, optionally, reacting said complex as claimed in claim 1 wherein X and Y are each nitrato with an alkali metal salt of a monocarboxylic acid so as to produce a complex as claimed in claim 1 in which one of X and Y is nitrato and the other is monocarboxylato, or reacting said complex as claimed in claim 1 wherein each of X and Y is nitrato with a monocarboxylic acid, a dicarboxylic acid, or an alkali metal salt thereof, so as to produce a complex as claimed in claim 1 wherein each of X and Y is monocarboxylato or X and Y considered together represent dicarboxylato.

24. A process as claimed in claim 23, wherein the starting compound of formula:

30

nh3 ococh^

nh3 ococh3

[ii]

40 has been prepared from a compound of the formula:

dc,

(ch2)

[hi]

by a procedure known per se.

25. A process as claimed in claim 23 and substantially as hereinbefore described.

26. A process for preparing a compound as claimed in claim 1 substantially as hereinbefore 45 described in any one of the foregoing Examples.

10

GB 2 074 567 A 10

10

27. A pharmaceutical or veterinary formulation comprising a complex as claimed in any one of claims 1 to 22 formulated for pharmaceutical or veterinary use, respectively.

28. A formulation as claimed in claim 27 and in unit dosage form.

29. A formulation as claimed in claim 27 or claim 28 also comprising a pharmaceutically acceptable or veterinarily acceptable, respectively, diluent, carrier or excipient.

30. A formulation as claimed in claim 27 and substantially as hereinbefore described.

31. A complex as claimed in any one of claims 1 to 22 or a formulation as claimed in any one of claims 27 to 30 for use in producing an anti-tumour activity in an animal.

32. A complex of the formula:

+ —

NH3 OCOCH3

10

(ay.

N«3 OCOCH3

wherein n and m are as defined in claim 1.

Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1981. Published by the Patent Office, 25 Southampton Buildings. London. WC2A 1AY, from which copies may be obtained.